Rabbits develop aortic atherosclerosis when fed a diet high in cholesterol. The types of lesions closely resemble types I-III atherosclerotic lesions in man. Recently we have demonstrated that mice transgenic with the gene encoding the enzyme lecithin:cholesterol acyl transferase have a striking increase in the concentration of high density lipoproteins. Since rabbit lipoprotein metabolism and susceptibility to dietary atherosclerosis more closely parallels that of man, we have undertaken the generation of rabbits transgenic for the human enzyme lecithin:cholesterol acyl transferase. We have generated 3 founder lines of rabbits integrating and expressing this gene. As with mice and man, the principal sites of synthesis are the liver and brain. The total and high density lipoprotein cholesterol and apolipoprotein A-I concentrations are increased 2-3 fold that of controls in the highest level of expression. In addition, there is a virtual disappearance in the concentration of the apolipoprotein B- containing particles. Metabolic turnover studies indicate that these changes in the particle concentrations of these particles is due to altered clearance from the circulation. The altered metabolism of these particles is directly correlated with the extent of expression of this enzyme. Rabbits with high, intermediate, and low levels of plasma lecithin:cholesterol acyl transferase expression have parallel degrees of alteration in the fractional catabolic rates of these particles from the circulation. Nontransgenic rabbits fed a high cholesterol diet have a marked increase in the concentration of the atherogenic very low, intermediate, and low density lipoproteins. In contrast, rabbits transgenic with human lecithin:cholesterol acyl transferase have substantially higher concentrations of high density lipoproteins and lower concentration in the atherogenic very low, intermediate, and low density lipoprotein particles. Since rabbits, like man, express the plasma cholesteryl ester transfer protein, we are currently evaluating the impact that these changes have on the development of atherosclerosis.